Abstract Integrated control of metabolism requires inter-organ communication in the peripheral tissues; this crosstalk is largely orchestrated by secreted hormones. Our long-term goal is to understand hormonal control of energy homeostasis. This proposal is a competitive renewal of a continuing research project focusing on a conserved family of secreted plasma proteins we identified, the C1q/TNF-related proteins (CTRPs). In the last decade, we have provided new and important knowledge on the roles and contributions of various CTRP hormones to whole-body glucose and lipid metabolism. In the next budget cycle, we will focus our studies on CTRP6, a protein with fundamentally different modes of action compared to other CTRPs characterized to date. Our preliminary studies on CTRP6, combined with recent studies of other CTRP family members, has led to the Yin and Yang concept, in which different CTRPs function as positive or negative regulators of substrate metabolism. The central hypothesis, based on gain- and loss-of-function mouse models, is that CTRP6 functions as a negative physiological regulator of glucose metabolism. We propose two specific aims toward understanding the mechanisms by which CTRP6 negatively regulates glucose metabolism at the tissue (Aim 1) and cellular (Aim 2) levels. We expect Aim 1 and Aim 2 to provide critical insights into metabolic gene circuits and signaling networks directly regulated by CTRP6 in adipocytes, skeletal muscle, and liver to control systemic energy metabolism. Since over-activation of the CTRP6-regulated pathways contributes to obesity-linked insulin resistance and diabetes, our studies have the potential to provide insights that lead to innovative strategies to reverse or mitigate metabolic disease outcomes in clinical settings.